Fibroblast growth factor 23 (FGF23) is a hormone with a central role in regulating circulating phosphate (Pi) levels and vitamin D metabolism. Several human diseases are characterized by FGF23 excess, including X-linked hypophosphatemia, autosomal dominant hypophosphatemic rickets, and tumor-induced osteomalacia. These diseases are characterized by growth failure, severe bone disease, and myopathy. FGF23 deficiency causes hyperphosphatemic familial tumoral calcinosis, characterized by calcium deposition in soft tissues and aberrant bone growth. While there is growing understanding of the role of FGF23 in disease, its role in maintaining Pi and vitamin D homeostasis in the healthy state is less well-understood. In particular, the role of FGF23 in regulating bone mineralization during childhood growth has not been well-explored. Additional gaps in knowledge include the age- and pubertal-stage variation in circulating FGF23 levels and the identification of the primary stimulus for FGF23 secretion in the healthy state. This proposal aims to address these gaps in order to further understand the function and regulation of this critical hormone. We will recruit 100 healthy girls, aged 9-18 years, for a cross-sectional study of circulating FGF23 levels and bone mineralization. We will obtain bone imaging by both dual-emission X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography. We will examine the association of FGF23 with measures of bone mineral density, bone microarchitecture, and bone strength. We will obtain bone age x- rays and assess pubertal stage on physical exam and, using regression analyses, determine what, if any, variation in FGF23 levels exists by chronological age and/or pubertal stage. We will also measure circulating levels of other key factors in bone mineral metabolism including calcium, Pi, 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D, parathyroid hormone, and bone turnover markers. 30 pre-pubertal and early-pubertal girls with vitamin D deficiency (25OHD level 20 ng/mL) will be co-enrolled in a prospective, randomized, placebo-controlled trial and treated with ergocalciferol 50,000 international units weekly or placebo for 16 weeks. We will examine the change in circulating FGF23 with area-under-the-curve analyses. These studies will provide key data regarding FGF23 physiology in pediatric populations which will help guide identification of mineral ion disorders and may suggest new treatment modalities. In addition, an improved understanding of the regulation of bone mineralization may translate into novel therapies for optimizing bone mineral density and thus fracture prevention throughout the lifespan. PUBLIC HEALTH RELEVANCE: Fibroblast growth factor 23 (FGF23) is a hormone which regulates phosphate and vitamin D metabolism; FGF23 may also be critical for normal bone development independent of its phosphate and vitamin D effects. While its role in several rare diseases is increasingly well-described, less is known about its function and regulation in healthy people, particularly in children. The research described in this proposal will help better define the function of FGF23 in healthy children to enhance our understanding of bone and mineral metabolism and bone mass accrual during childhood.